Epstein Barr virus (EBV) is a cause of infectious mononucleosis and is associated with a number of cancers including nasopharyngeal carcinoma, Burkitt lymphoma and lymphoma in transplant recipients. Elevated IgA antibodies, indicative of ongoing exposure to Epstein-Barr virus (EBV), are high-risk biomarkers for nasopharyngeal carcinoma (NPC), an EBV-related epithelial tumor. However, protective biomarkers that limit exposure to the virus have not been defined. We evaluated whether antibodies that can neutralize EBV infection by targeting glycoproteins involved in viral cell entry, such as antibody to EBV glycoprotein 350 (gp350), were associated with lower risk of NPC. In a prospective cohort of 2,557 individuals from 358 high-risk NPC multiplex families in Taiwan, we identified 21 incident NPC cases and 50 disease-free controls. To complement data from high-risk families, we further identified 30 prevalent NPC cases and 50 healthy controls from the general Taiwanese population. We quantified EBV-neutralizing antibody, antibodies against EBV glycoproteins involved in B-cell and epithelial cell entry, and anti-EBNA1 IgA, a high-risk NPC biomarker. EBV-neutralizing antibodies blocking B-cell infection and anti-gp350 antibodies were present at significantly higher levels in disease-free controls compared with incident NPC cases (P < 0.03). Family members with both low EBV-neutralizing potential and elevated EBNA1 IgA had a 7-fold increased risk of NPC (95% CI, 1.9-28.7). Neutralizing antibodies against epithelial cell infection did not differ between incident cases and disease-free controls. Anti-glycoprotein antibody levels measured at diagnosis (prevalent NPC) were significantly higher than levels measured prior to diagnosis (P < 0.01). Thus, elevated titers of EBV-neutralizing antibody and anti-gp350 antibody were low-risk biomarkers for NPC. These data suggest that a vaccine that induces potent EBV gp350 and B-cell-neutralizing antibodies could reduce the risk of EBV-related cancers such as NPC. EBV can be associated with severe infectious mononucleosis, chronic active disease, and various tumors. In most of these cases a cause for these severe EBV disorders in not known. We reported seven patients with GATA2 deficiency that developed severe EBV disease. Three presented with EBV infectious mononucleosis requiring hospitalization, 1 had chronic active EBV disease (B-cell type), 1 had EBV-associated hydroa vacciniforme-like lymphoma with hemophagocytic lymphohistiocytosis, and 2 had EBV-positive smooth muscle tumors. Four of the 7 patients had severe warts and 3 had disseminated nontuberculous mycobacterial infections. All of the patients had low numbers of monocytes, B cells, CD4 T cells, and natural killer cells. All had elevated levels of EBV in the blood; 2 of 3 patients tested had expression of the EBV major immediate-early gene in the blood indicative of active EBV lytic infection. Mean plasma levels of tumor necrosis factor alpha, interferon-gamma, and interferon gamma-induced protein 10 were higher in patients with GATA2 deficiency than in controls. GATA2 is the first gene associated with EBV hydroa vacciniforme-like lymphoma. GATA2 deficiency should be considered in patients with severe primary EBV infection or EBV-associated cancer, especially in those with disseminated nontuberculous mycobacterial disease and warts.